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Neuroscience 130 (2005) 567–580 REVIEW GLUTAMATE AND GABA RECEPTOR SIGNALLING IN THE DEVELOPING BRAIN R. LUJÁN,a* R. SHIGEMOTOb AND G. LÓPEZ-BENDITOc Key words: neurotransmitter receptors, AMPA, NMDA, kainate GABAB receptors, mGlu receptors, development. a Facultad de Medicina and Centro Regional de Investigaciones Biomédicas, Universidad de Castilla-La Mancha, Campus Biosanitario, Avda. de Almansa s/n, 02006 Albacete, Spain Contents Developmental expression of neurotransmitter receptor subunits 568 AMPA receptor subunits 568 NMDA receptor subunits 568 Kainate receptor subunits 568 mGlu receptor subtypes 569 570 GABAA receptor subunits GABAB receptor subunits 570 Neurotransmitter receptor signaling in cell proliferation 570 Involvement of neurotransmitter receptor in neuronal migration 572 Radial migration 572 Tangential migration 572 Role of neurotransmitter receptors in early neuronal differentiation 573 Neurotransmitter receptor signaling during synaptogenesis 574 Acquisition and localization of neurotransmitter receptors at synapses 574 Glutamatergic synapses 574 GABAergic synapses 576 Concluding remarks 576 Acknowledgments 576 References 576 b Division of Cerebral Structure, National Institute for Physiological Sciences, CREST Japan Science and Technology Corporation, Myodaiji, Okazaki 444-8585, Japan c Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Campus de San Juan, 03550 San Juan de Alicante, Spain Abstract—Our understanding of the role played by neurotransmitter receptors in the developing brain has advanced in recent years. The major excitatory and inhibitory neurotransmitters in the brain, glutamate and GABA, activate both ionotropic (ligand-gated ion channels) and metabotropic (G protein-coupled) receptors, and are generally associated with neuronal communication in the mature brain. However, before the emergence of their role in neurotransmission in adulthood, they also act to influence earlier developmental events, some of which occur prior to synapse formation: such as proliferation, migration, differentiation or survival processes during neural development. To fulfill these actions in the constructing of the nervous system, different types of glutamate and GABA receptors need to be expressed both at the right time and at the right place. The identification by molecular cloning of 16 ionotropic glutamate receptor subunits, eight metabotropic glutamate receptor subtypes, 21 ionotropic and two metabotropic GABA receptor subunits, some of which exist in alternatively splice variants, has enriched our appreciation of how molecular diversity leads to functional diversity in the brain. It now appears that many different types of glutamate and GABA receptor subunits have prominent expression in the embryonic and/or postnatal brain, whereas others are mainly present in the adult brain. Although the significance of this differential expression of subunits is not fully understood, it appears that the change in subunit composition is essential for normal development in particular brain regions. This review focuses on emerging information relating to the expression and role of glutamatergic and GABAergic neurotransmitter receptors during prenatal and postnatal development. © 2005 IBRO. Published by Elsevier Ltd. All rights reserved. The ability of our nervous system to learn, change and respond to the environment, reflects an underlying capability of neurons to dynamically alter the strengths of their connections. These connections, called synapses, are highly specialized sites of contact between presynaptic nerve terminals and postsynaptic neurons. Synapses contain a large variety of molecules at very high local densities, including neurotransmitter receptors, associated structural proteins and signaling molecules, whose precise organization gives rise to proper function. Among these synaptic molecules, neurotransmitter receptors will ultimately define the functionality of a synapse. Furthermore, many of the observed changes in synaptic transmission efficacy, that play a central role in processes such as learning and memory or neurodegeneration, are mediated by neurotransmitter receptors. The present view of the central nervous system (CNS) has developed dramatically over the past few years and new principles regarding the role of neurotransmitter receptors in the developing CNS are beginning to emerge. The development of the CNS results from a well charac- *Corresponding author. Tel: ⫹34-967-599200x2933; fax: ⫹34-967599327. E-mail address: [email protected] (R. Luján). Abbreviations: AMPA, ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; CNS, central nervous system; CP, cortical plate; CR, CajalRetzius; GABA, ␥-aminobutyric acid; iGlu, ionotropic glutamate; IZ, intermediate zone; mGlu, metabotropic glutamate; NMDA, N-methylD-aspartate; RMS, rostral migratory stream; SVZ, subventricular zone; VZ, ventricular zone. 0306-4522/05$30.00⫹0.00 © 2005 IBRO. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.neuroscience.2004.09.042 567 568 R. Luján et al. / Neuroscience 130 (2005) 567–580 terized temporo-spatial pattern of events that begins with neuronal proliferation, followed by migration, differentiation, and ending with synapse formation and circuit refinements. A growing body of evidence suggests that each step in that developmental sequence of the CNS involves both the appropriate expression and function of neurotransmitters and their receptors. Although glutamate and ␥-aminobutyric acid (GABA) are the primary excitatory and inhibitory neurotransmitters in adulthood, it is now fairly well established that both are abundant and widespread early in embryonic life (Miranda-Contreras et al., 1998, 1999; Benı́tez-Diaz et al., 2003). Glutamate and GABA mediate their actions by the activation of ionotropic (ligandgated ion channels) and metabotropic (G protein-coupled) receptors. Three subclasses of ionotropic glutamate (iGlu) receptors are known and are named after their selective agonists: i) ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), ii) N-methyl-D-aspartate (NMDA) and iii) kainate receptors (Hollmann and Heinemann, 1994). Sixteen functional subunits may assemble in tetrameric complexes to form the following receptors: GluR1–GluR4 for AMPA (that occur in two alternatively spliced versions, flip and flop); GluR5–GluR7 and KA1–KA2 for kainate; and NR1, NR2A–NR2D and NR3A–B for NMDA receptors (Hollmann and Heinemann, 1994). The metabotropic glutamate (mGlu) receptors consist of at least eight different subtypes (mGlu1–mGlu8), that have been classified into three groups based on their sequence homology, pharmacological profile and coupling to intracellular transduction pathways (Pin and Duvoisin, 1995; Conn and Pin, 1997). Group I mGlu receptors consist of mGlu1, mGlu5 and their splice variants (mGlu1␣, , c, d and mGlu5a,b); group II receptors include mGlu2 and mGlu3; and group III consists of mGlu4, mGlu6, mGlu7 and mGlu8, and some splice variants. Based on the presence of eight subunit families consisting of 21 subunits (␣1-6, 1-4, ␥1– 4, ␦, ⑀, , , 1-3), the ionotropic GABA receptors (GABAA receptors) display an extraordinary structural heterogeneity. It is thought that most functional GABAA receptors in vivo are formed upon co-assembly of ␣-, -, and ␥-subunits (Macdonald and Olsen, 1994). The metabotropic GABA receptors (GABAB receptors) consist of two subunits: GABAB1, which exists in alternatively spliced forms designated 1a, b, c, d and e, and GABAB2 (reviewed by Billinton et al., 2001; Bowery et al., 2002). Physiological responses following activation of GABAB receptors require the co-assembly of GABAB1 and GABAB2 (reviewed by Couve et al., 2000; Bowery et al., 2002). In this review, we summarize the current knowledge on the involvement of neurotransmitter receptors in neuronal signaling during development. We will focus on glutamate and GABA receptors, which are inextricably linked in the control of neuronal excitability, and discuss issues concerning their expression and role in the developing brain. Firstly, we will provide an overview of the diversity of glutamate and GABA receptor subunits and their developmental expression pattern, and then discuss their potential functions in the brain from proliferation to synapse formation. Developmental expression of neurotransmitter receptor subunits One indicator of the functional importance of neurotransmitter receptor subunit diversity comes from examining the subunit mRNA or protein changes seen during development. Although the exact changes in subunit expression vary with brain region, it now appears that many different types of neurotransmitter receptors are present in the embryonic brain, while others are dominant in the postnatal brain or in the adult brain. AMPA receptor subunits. The GluR1 subunit is detected in the whole brain at embryonic day E15, and levels increase progressively during late embryonic and early postnatal days (Martin et al., 1998). Regionally, GluR1 increases in the cerebral cortex but decreases in the striatum with postnatal development. In the cerebellum, GluR1 is expressed transiently at particular time points postnatally, by both granule and Purkinje cells, but from P21 onwards these neurons have very low GluR1 levels (Martin et al., 1998; Fig. 1). The GluR2/3 subunits are also expressed in embryonic development, whereas the GluR4 subunit is mainly expressed in the late postnatal development and adult (Hall and Bahr, 1994; Furuta and Martin, 1999; Metin et al., 2000; Fig. 1). Concerning the isoforms of AMPA receptors, flip variants expression dominates before birth and continues to be expressed into adulthood, whereas flop variants are in low abundance before P8 and are up-regulated to about the same level as the flip forms in adulthood (Hollmann and Heinemann, 1994; Fig. 1). NMDA receptor subunits. The functional NR1 subunit is ubiquitously present in the brain throughout pre- and postnatal development (Fig. 1), while the modulatory subunits (NR2A-D) are differentially expressed (Watanabe et al., 1993; Takai et al., 2003). The NR2A subunit is expressed postnatally and widely in the brain while the NR2B subunit is detected throughout the entire embryonic brain, with a restricted expression to the forebrain at postnatal stages (Fig. 1). The NR2C subunit appears postnatally and is prominent in the cerebellum; the NR2D subunit is mainly present in the diencephalon and the brainstem at embryonic and neonatal stages (Watanabe et al., 1993; Takai et al., 2003). The NR3 subunit is abundant within the late prenatal and early postnatal brain development (Sun et al., 1998). Kainate receptor subunits. The mRNA for all kainate receptor subunits, except the KA-1 subunit, can be detected in the embryonic brain by E12 (Bahn et al., 1994). All subunits undergo a peak in their expression in the late embryonic and early postnatal period (Fig. 1). At the regional level, the GluR5 subunit shows a peak of expression around the period of birth in the sensory cortex, in CA1 hippocampal interneurons (stratum oriens), the septum, and in the thalamus, while the GluR6 subunit shows a prenatal expression peak in the neocortical cingulate gyrus. The KA-1 subunit appears with the development of the hippocampus and remains largely confined to discrete R. Luján et al. / Neuroscience 130 (2005) 567–580 569 Fig. 1. Schematic representation of the expression of glutamate and GABA receptors throughout the developing rat cerebral cortex. The gradient in the gray scale shows the relative differences in the expression between the distinct subunits for each subclass of iGlu receptors, the distinct subtypes of mGlu receptors, and the distinct subunits of GABAB receptors, but not between the different receptor subclasses or subfamilies; for details see text. Differences in the onset of expression between substructures, e.g. cortical layers, have not been considered; for details see text. NMDA receptors are expressed relatively earlier than AMPA and kainate receptors. Regarding metabotropic receptors, mGlu1 seems to be expressed relatively earlier than the other seven subtypes, whereas the GABAB1 subunit of the GABAB receptors exceed that of the GABAB2 subunit during embryonic development but equalizes in the adult brain. Embryonic and postnatal ages are expressed in days. areas such as the CA3 region, the dentate gyrus, and subiculum, whereas the KA-2 subunit is found throughout the CNS from early embryonic stages (Fig. 1), remaining constant until adulthood (Bahn et al., 1994). mGlu receptor subtypes. The expression of mGlu receptor subtypes is differentially regulated during development, showing distinct regional and temporal profiles. The two receptor subtype of group I, mGlu1 and mGlu5, are detected during embryonic development (Shigemoto et al., 1992; López-Bendito et al., 2002a; Fig. 1), albeit at low levels. However, while the level of mGlu1 expression gradually increases during early postnatal days (Shigemoto et al., 1992; López-Bendito et al., 2002a), mGlu5 expression increases perinatally, peaking around the second postnatal week and decreases thereafter to adult levels (Catania et al., 1994; Romano et al., 1996, 2002; Fig. 1). This different expression pattern is also detected at the level of their isoforms. Thus, it seems that mGlu1␣ predominates during development, as mGlu1 and mGlu1c is mostly not detected until adulthood (Casabona et al., 1997). In contrast, the change in expression of mGlu5 is associated with a decline in the mGlu5a splice variant and an increase in mGlu5b, which dominates in adulthood (Minakami et al., 1995; Romano et al., 1996, 2002). 570 R. Luján et al. / Neuroscience 130 (2005) 567–580 In addition, group II mGlu receptors are also differentially expressed. In the brain, mGlu2 mRNA expression is low at birth and increases during postnatal development, whereas mGlu3 is highly expressed at birth and decreases during maturation to adult levels of expression (Catania et al., 1994; Fig. 1). Finally, with reference to group III mGlu receptors, the mRNA and protein expression for mGlu4 is low at birth and increases during postnatal development (Catania et al., 1994; Elezgarai et al., 1999; Fig. 1). Similarly, mGlu7a levels are highest at P7 and P14, and then decline thereafter in cortical regions (Bradley et al., 1998). GABAA receptor subunits. GABAA receptor subunit expression is differentially regulated during brain development, with each subunit exhibiting a unique regional and temporal developmental expression profile. Some of the 21 GABAA subunits dominate expression during embryonic development (e.g. ␣2, ␣3, and ␣5), whereas others dominate postnatally or in the adult brain (Laurie et al., 1992; Fritschy et al., 1994). For example, the expression of the ␣1 subunit is low at birth, but increases during the first postnatal week, whereas the ␣2 subunit decreases progressively (Fritschy et al., 1994). Additionally, the ␣5 subunit is found throughout pre- and postnatal development (Killisch et al., 1991). The 2/3 subunits are ubiquitously expressed during development, indicating their association with ␣ subunits in distinct receptor subtypes (Fritschy et al., 1994). The ␥1 and ␥3 subunits expression levels drop markedly during development, whereas ␥2 expression is widespread and remains mostly constant throughout development (Fritschy et al., 1994). Although the significance of the differential expression of GABAA receptor subunits is not completely understood, it seems that subunit switching in certain brain regions is essential for normal development (Culiat et al., 1994; Gunther et al., 1995). GABAB receptor subunits. In situ hybridization and immunohistochemical studies have defined a pattern of early and strong GABAB1 receptor expression in discrete brain regions during embryonic development (López-Bendito et al., 2002b, 2003, 2004b; Kim et al., 2003; Martin et al., 2004; Panzanelli et al., 2004). GABAB1 receptor mRNA is intensely expressed by E11, and at E12 is detected in the hippocampal formation, cerebral cortex, intermediate and posterior neuroepithelium, and the pontine neuroepithelium (Kim et al., 2003; Martin et al., 2004). Furthermore, the most widely studied isoforms of the GABAB1 subunit, GABAB1a and GABAB1b, seem to be developmentally regulated, with GABAB1b being the most abundant isoform in the adult, while GABAB1a dominates during postnatal development (Fritschy et al., 1999; Fig. 1). However, GABAB2 receptor mRNA and protein are not detected at the same time period, as the expression of the GABAB1 subunit, whose isoforms greatly exceed that of the GABAB2 subunit during embryonic development but equalizes in most regions in the adult brain (Kim et al., 2003; López-Bendito et al., 2002b, 2004b; Martin et al., 2004; Panzanelli et al., 2004; Fig. 1). Thus it is likely that the GABAB1 subunit is more important than the GABAB2 subunit in the early development of the CNS. Indeed, it appears that GABAB receptor subunits are not coordinately regulated during development. Despite the fact that functional GABAB receptor requires heterodimerization of GABAB1 and GABAB2 subunits, the expression of each of them is under independent control during embryonic development (Martin et al., 2004). Neurotransmitter receptor signaling in cell proliferation Proliferation of neuronal progenitors is one of the fundamental developmental processes responsible for generating the correct number of cells of each type in the correct sequence in the brain. Both cell-intrinsic and -extrinsic factors contribute to changes in cell production and affect cerebral cortical growth. Among other extracellular molecules, neurotransmitter receptors have been implicated in the extrinsic regulation of cell proliferation in the developing telencephalon (see review by Cameron et al., 1998; Nguyen et al., 2001; Owens and Kriegstein, 2002). Functional iGlu receptors emerge during terminal cell division and early neuronal differentiation of rat neuroepithelial cells (Maric et al., 2000). Several studies have also shown that both NMDA and non-NMDA glutamate receptors are expressed in early postmitotic neurons (see review by Lauder, 1993; Bardoul et al., 1998), and that glutamate can inhibit DNA synthesis in cells proliferating at the cortical neuroepithelium when AMPA/kainate receptor are activated (LoTurco et al., 1995). However, proliferation of striatal neuronal progenitors is promoted by an NMDA receptor-dependent mechanism but not AMPA/kainate receptors at the ventral telencephalon (Luk et al., 2003). AMPA responses are first observed in terminally dividing neuronal progenitors which begin to express Tuj1 (an antigen which is expressed by neuronal precursors) near the time of terminal division. Postmitotic neurons express both AMPA/kainate and NMDA receptors (Maric et al., 2000). Taken together these results suggest that the appearance of functional iGlu receptors may regulate the transition from proliferation to postmitotic neuronal differentiation. The role of NMDA receptor activation controlling cell proliferation has also been shown to occur in brain regions that retain a neurogenic population of cells through life. This is the case in the dentate gyrus of the hippocampus, in rodents (Cameron et al., 1995), primates (Gould et al., 1998) and human (Eriksson et al., 1998). Several in vivo studies have shown that blockage of NMDA receptors during either the first postnatal week or in adult rats, increases cell proliferation in the hippocampus; affecting mainly granule cells (Gould et al., 1994; Cameron et al., 1995). However, the mechanisms by which glutamate decreases dentate gyrus cell proliferation remains unknown. In relation to the possible involvement of mGlu receptors, it has also been shown the presence of mGlu5 receptor in zones of active neurogenesis both in the prenatal and postnatal brain (Di Giorgi Gerevini et al., 2004). R. Luján et al. / Neuroscience 130 (2005) 567–580 571 Fig. 2. Neurotransmitter receptors are involved in the Prolif and migration of cortical neurons. AMPA responses are first observed in terminally dividing neuronal progenitors while postmitotic neurons (green cells) express both AMPA/kainate and NMDA receptors. Activation of GABA and Glu receptors by GABA and Glu, respectively, has been shown to shorten the cell cycle of VZ progenitors (black circled positive symbol), while the Prolif in the SVZ is markedly decreased in response to GABA (black circled negative symbol). Neurotransmitter receptor activation has been reported to influence neuronal migration of cortical neurons at early stages of development. Thus, GABAC and GABAB-like receptor activation (red circled positive symbol) stimulates migration of neurons from the VZ and IZ, respectively, whereas GABAA receptor activation arrests migration as neurons approach their target destinations in the CP. The U-shape discontinuous line with arrows represents the direction followed by the cells types during Prolif and migration. The gradient in the background color represents the different cortical layers. Glu, glutamate; MZ, marginal zone; Prolif, proliferation; RG, radial glia. Regarding the GABAergic system, several types of GABAA receptor transcripts and subunits have been described as components of functional GABAA receptors in rat neuroepithelial cells, neuroblasts and glioblasts, during spinal and cortical neurogenesis (LoTurco et al., 1995; Ma and Barker, 1995; Ma et al., 1998; Serafini et al., 1998; Verkhratsky and Steinhauser, 2000). In precursor cells, in the neocortical proliferative zone, activation of GABAA receptors has been shown to influence DNA synthesis (LoTurco et al., 1995; Haydar et al., 2000). A more recent study has pointed to a more complicated scenario. Using organotypic mouse slice cultures in which the spatial separation between the ventricular zone (VZ) and subventricular zone (SVZ) of the cerebral cortex has been maintained, inherent differences between VZ and SVZ progenitors in their physiological responses to GABA or glutamate were observed (Haydar et al., 2000). Exogenously applied GABA and glutamate shortened the cell cycle of VZ pro- genitors; this effect suggesting a mediation by GABAA or AMPA/kainate receptors. Surprisingly, in contrast to these findings, proliferation in the SVZ markedly decreased in response to GABA, glutamate, and their agonists (Fig. 2). Thus, depending on the cortical compartment, GABA and glutamate have differential effects on cortical cell proliferation. Altogether, these results suggest that in cultured progenitor cells of the developing neocortex, GABA and glutamate regulate cell proliferation by providing a feedback signal that controls division (Fig. 2). Additionally, a GABA-dependent cell proliferation has also been demonstrated in the hippocampus (Ben-Yaakov and Golan, 2003). The exact mode of GABA or glutamate action is still unresolved. Nevertheless, functional GABAergic-signaling components among differentiating neurons and their capacity to release GABA from both cell body and growth cone compartments emerge during neuronal lineage pro- 572 R. Luján et al. / Neuroscience 130 (2005) 567–580 gression (Maric et al., 2001). Those postmitotic cells could be the source of GABA or glutamate that leads to the activation of GABA and glutamate receptors expressed by mitotic cells in the proliferative zones. Regardless of the subcellular compartment, it seems that at least GABA can be released in a paracrine manner to active its receptors (Demarque et al., 2002), as synapses are still not present. Other interesting questions as how are GABA and glutamate concentrations regulated or what kind of intracellular signaling mechanisms are involved in their activation are still unanswered. tility and migration in both dissociated cells and organotypic slice cultures (Behar et al., 1996, 2000, 2001). In cultured rat brain slices, it has been determined that GABAC and GABAB-like receptor activation stimulates migration of neurons from the VZ and IZ, respectively, whereas GABAA receptor activation arrests migration as neurons approach their target destinations in the CP (Behar et al., 1998). Altogether these data show that activation of neurotransmitter receptors, independent of the brain area or neuronal phenotype, plays a role in controlling the migration of neurons. Involvement of neurotransmitter receptor in neuronal migration Tangential migration. The cellular and molecular mechanisms controlling tangential migration of cortical interneurons are still relatively unknown. It has been suggested that activation of AMPA receptors leads to neurite retraction in tangentially migrating interneurons (Poluch et al., 2001). In addition, tangentially migrating cells in the cerebral cortex posses functional NMDA, non-NMDA and GABAA receptors whose activation leads to changes in [Ca2⫹]i (Soria and Valdeolmillos, 2002). However, the relationship between these changes in [Ca2⫹]i signaling and the actual process of tangential migration is still unclear. Several studies though have provided some illuminating ideas on the role of GABA receptors in tangential migration. Interestingly, one of these studies involved the activation of neurotransmitter receptors and the end result, in particular, reinforced the role of GABAB receptors in migration of neurons (López-Bendito et al., 2003). Using in vitro embryonic rat organotypic cultures, in combination with immunohistochemical techniques, it was shown that blockade of GABAB receptor modified the distribution of tangential migratory interneurons within the cortex (LópezBendito et al., 2003; Fig. 3). Additionally, other studies have shown the functionality of some of these neurotransmitter receptors, in the tangentially migratory interneurons (Metin et al., 2000; Soria and Valdeolmillos, 2002). For example, GABAergic calbindin-positive IZ cells seem to express inwardly rectifying calcium-permeable AMPA receptors, but not NMDA receptors (Metin et al., 2000; Fig. 3). Likewise, these cells displayed electrophysiological responses to GABAA agonists. Another population of neurons that adopt a tangential mode of migration to reach their final target is the precursors of olfactory interneurons. These interneurons are born in the embryonic subpallium (Altman, 1969; Lois and Alvarez-Buylla, 1994) and their migration continues through adulthood, providing a constant supply of new GABAergic local circuit neurons to the olfactory bulb (Lois and Alvarez-Buylla, 1994). Migration of olfactory interneurons in the adult occurs along a highly restricted route termed the rostral migratory stream (RMS; Lois and Alvarez-Buylla, 1994; Kornack and Rakic, 2001). A recent study pointed out the possibility that GABA may also affect these neuronal progenitors via the activation of specific receptors (Wang et al., 2003). Every neuronal progenitor responded to GABA via picrotoxin-sensitive GABAA receptor activation, demonstrating that the neuronal progenitors of the SVZ/RMS contain and are depolarized by GABA. After division, most cortical neurons migrate from their site of origin to their final destination in the cerebral cortex. This neuronal movement is essential for the establishment of normal brain organization (see for instance Hatten, 1999). In the developing cerebral cortex, glutamatergic projecting neurons are primarily generated in the VZ and then move to the developing cortical plate (CP) by means of “radial migration” (see review by Marı́n and Rubenstein, 2001). Most GABAergic interneurons, however, originate mainly in the medial ganglionic eminence of the ventral telencephalon and follow tangential migratory routes through the intermediate zone (IZ) to reach the cortex (see review by Parnavelas, 2000; Marı́n and Rubenstein, 2001; Fig. 3). However, the caudal ganglionic eminence has been recently demonstrated to give rise to a distinct population of GABAergic interneurons (Nery et al., 2002; López-Bendito et al., 2004a). Neurotransmitter receptor activation has been reported to influence neuronal migration of cortical neurons at early stages of development. The presence of some of these neurotransmitter receptors in the embryonic cerebral cortex has been shown by in situ hybridization and immunohistochemistry (Behar et al., 2001; López-Bendito et al., 2002b; Fig. 3). In the following sections, we will review the role of neurotransmitter receptors in the processes of neuronal migration in the forebrain. Radial migration. Due to its early expression pattern, glutamate is a likely candidate to play a role as a chemoattractant signal in the developing mouse cerebral cortex. An assay measuring the effects of glutamate on the migration of acutely dissociated murine embryonic cortical cells, revealed stimulation of the migration of cortical neurons to a 10-fold greater extent than GABA (Behar et al., 1999). In the cerebellum, if NMDA receptors are blocked by specific antagonists or by high Mg2⫹ concentration, the granule cell migration from the external to the internal granule layer is retarded (Rossi and Slater, 1993). Conversely, an increase of NMDA or glycine concentration increases this process (Komuro and Rakic, 1993). Some illuminating results on the role of neurotransmitter receptors on cortical radial migration, came from a series of pharmacological studies, which showed the influence of the activation of GABA receptors in neuronal mo- R. Luján et al. / Neuroscience 130 (2005) 567–580 573 Fig. 3. Neurotransmitter receptors are involved in the tangential migration of cortical interneurons. Tangentially migrating interneurons express iGlu receptors in addition to GABA receptors (see legend in Fig. 3B). (A) Expression of GABAB1 receptor subunit (green) in migratory interneurons coming from the ganglionic eminence, labeled in red with a cell-tracker (CMTMR). Note the high expression of this receptor subunit in the plasma membrane and cytoplasm of tangentially orientated cells in the LIZ (insets) and in cells in the CP and MZ. (B) Diagram showing the expression and distribution of iGlu receptors and GABAB receptors in CP cells and tangentially migrating interneurons. CP cells may release glutamate that could activate (black positive symbol) iGlu receptors expressed in the tangentially migrating interneurons. This activation may lead to GABA release from these cells and to the activation of its GABA receptors and those expressed in nearby cells. The blockade of GABAB receptor leads to an accumulation of interneurons at the proliferative zones of the cortex suggesting that the activation of this receptor is important for the transition of the interneurons from the LIZ to the CP of the cortex. MZ, marginal zone. This thus directly suggests that this event may constitute the basis for a paracrine signal among neuronal progenitors to dynamically regulate their proliferation and/or migration. Role of neurotransmitter receptors in early neuronal differentiation In addition to proliferation and migration, several aspects of neuronal differentiation appears to be regulated by early glutamate- and GABA-mediated signaling. For instance, one of the most important cell types during early cortical neuronal differentiation are the Cajal-Retzius (CR) cells. Among the earliest generated population of neurons in the developing neocortex, CR cells have been implicated in regulating cortical lamination. In rodents, CR cells are transient, being present only up to 2–3 weeks after birth. They secrete reelin (Reln, an extracellular matrix molecule), whose absence in the mouse mutant reeler causes 574 R. Luján et al. / Neuroscience 130 (2005) 567–580 a severe cortical laminar disruption (see review by Frotscher, 1998; Curran and D’Arcangelo, 1998; Tissir and Goffinet, 2003). The molecular cascade acting downstream of Reln is just beginning to be understood (Walsh and Goffinet, 2000). However, the functional mechanisms that regulate Reln synthesis and secretion have been little explored. CR cells express diverse types of neurotransmitter receptors, including iGlu receptors and GABAA receptors (Schwartz et al., 1998; Mienville and Pesold, 1999). Recently, the expression of the mGlu receptor 1␣, mGlu1␣, in CR cells (Martı́nez-Galán et al., 2001; López-Bendito et al., 2002a) and the existence of functional mGlu1 in layer I cells of the postnatal mouse cerebral cortex was established (Martı́nez-Galán et al., 2001). Postnatal CR cells incur a dramatic increase in their NMDA receptor density, which ultimately may trigger their death. The fact that in vivo pharmacological blockade of NMDA receptors curtailed the disappearance of CR cells (Mienville and Pesold, 1999) strongly supports such a hypothesis. Apart from the correct positioning and laminar acquisition of cortical neurons, glutamate causes a graded series of changes in pyramidal neuron cytoarchitecture inducing a selective inhibition in dendritic outgrowth and dendritic pruning at subtoxic levels. Some studies have also reported that NMDA receptor activation promotes neurite outgrowth from cerebellar granule cells (Pearce et al., 1987) and dendritic outgrowth and branching of hippocampal cells (Mattson et al., 1988; Brewer and Cotman, 1989; Wilson et al., 2000). Furthermore, GABAA receptor activation has also been shown to promote neurite outgrowth and maturation of GABAergic interneurons (Barbin et al., 1993; Marty et al., 1996). In addition it is seen to regulate the morphological development of cortical neurons through membrane depolarization and increases in [Ca2⫹]i (Maric et al., 2001). involvement of mGlu receptors in such processes is unknown, it has been recently suggested that they may also participate in synapse-stabilizing responses (Miskevich et al., 2002). Additionally, a description on the role of GABAA receptor subunits in synaptogenesis has also been extensively reviewed recently (see for instance Ben-Ari, 2002; Owens and Kriegstein, 2002; Fritschy et al., 2003; Meier, 2003). Altogether, those reviews outline that the assembly of CNS synapses likely involve a complex interplay of cell– cell adhesion, interneuronal signaling and sitespecific recruitment of protein complexes. Furthermore, activity-dependent mechanisms control postsynaptic level of neurotransmitter receptors, with different mechanisms used for the synaptic targeting of distinct receptor types. Much less is known, however, about the acquisition of different glutamate and GABA receptor subunits occurring during synapse formation, and how they accumulate and change at synapses to reach their final distribution pattern during synapse maturation and adulthood. In the next section, we will concentrate on such processes. Neurotransmitter receptor signaling during synaptogenesis Glutamatergic synapses. Electrophysiological and immunohistochemical studies have shown that NMDA receptors are expressed firstly in glutamatergic synapses. Early in postnatal development, and during development, synapses acquire AMPA receptors with little change in NMDA receptor numbers (Golshani et al., 1998; Petralia et al., 1999). With regard to their localization, during postnatal development and adulthood, AMPA and NMDA receptors are concentrated at the postsynaptic specialization (Fig. 4). However, while AMPA receptors seem to be evenly distributed along the postsynaptic specialization (Nusser et al., 1998b; Somogyi et al., 1998), NMDA receptors are preferentially distributed to the center of it (Somogyi et al., 1998; Racca et al., 2000). Interestingly, NMDA receptors have been found on membranes postsynaptic to GABAergic terminals (Fig. 4) in the adult hippocampus (Gundersen et al., 2004), though no information is yet available about the factors controlling their recruitment in inhibitory synapses during development. Finally, the acquisition and arrangement of kainate receptors at synapses remains to be fully established. It is well known, however, that the KA-1 and KA-2 subunits are located at synaptic sites, as well as at presynaptic sites in the adulthood (Darstein et al., 2003; Fig. 4). The establishment of neural networks begins with growing axons recognizing their postsynaptic targets, thus forming synaptic contacts. This process can be divided into two separate phases: the first one (synapse formation) comprises the establishment of functional synaptic communication, and the second phase (synapse maturation) comprises the functional and morphological differentiation of synapses; both phases requiring tight communication between pre- and postsynaptic elements. How specific pre- and postsynaptic elements are differentiated, how synaptic contacts are generated developmentally and how these synapses are remodeled and maintained in mature brain seems to be in part mediated by the action of neurotransmitter receptors. A complete description on the involvement of NMDA and AMPA receptors in the formation, stabilization, maturation and elimination of synapses has been extensively reviewed elsewhere (see for instance Bolton et al., 2000; Lee and Sheng, 2000; Zhang and Poo, 2001; Cohen-Cory, 2002; Garner et al., 2002). Although the Acquisition and localization of neurotransmitter receptors at synapses A critical aspect in the development of glutamatergic and GABAergic synapses is the progressive recruitment and subsequent accumulation of neurotransmitter receptors at their functional site. Such processes are important, because proper function of synaptic transmission at any given synapse, depends on adequate placement of neurotransmitter receptors of the appropriate number and type, in the neuronal membrane. The differential regulation of the distinct subunits during pre- and postnatal development (see Developmental expression of neurotransmitter receptor subunits) may favor the correct acquisition and accumulation processes of receptor complexes. R. Luján et al. / Neuroscience 130 (2005) 567–580 575 Fig. 4. Schematic diagrams showing the location of glutamate and GABA receptors at synapses in the cerebral cortex during postnatal development and adulthood. Panels A and B show the localization of glutamate receptors at excitatory and inhibitory synapses, respectively. Panels C and D show the localization of GABA receptors at excitatory and inhibitory synapses, respectively. The precise localization of the different glutamate and GABA receptor subunits varies among brain regions and cell types. Therefore, the schematic diagrams are not representative of all glutamatergic or GABAergic synapses. NMDA, AMPA and kainate receptors are concentrated in the postsynaptic specialization, as well as extrasynaptically (panel A). Early in postnatal development, and during development, synapses acquire AMPA receptors with little change in NMDA receptor numbers. However, group I mGlu receptors are absent from the postsynaptic specialization, occurring peri- or extrasynaptically (panel A). Group II mGlu receptors occur in the preterminal portion of axon terminal, whereas group III mGu receptors are found in the presynaptic active zone (panel A). During postnatal development, mGlu receptors progressively concentrate at those subcellular compartments to reach their final density in the adult brain. GABAA receptor subunits are concentrated at synapses opposite to GABA releasing terminals (panel D). In contrast, GABAB receptors can be present at preand postsynaptic sites (panels C and D). They are mainly found associated with glutamatergic synapses (panel C). The acquisition and distribution of mGlu receptors during development seems to be different to that described for iGlu receptors. This may be because mGlu receptors are absent from the postsynaptic specialization. Electrophysiological studies (Golshani et al., 1998) have shown that functional mGlu receptors are detected in cortical synapses from birth (approximately at the same time as functional NMDA receptors), although only after the first postnatal week could slow EPSPs mediated by mGlu receptors be evoked by high-frequency stimulation. Immunohistochemical studies have demonstrated that early in postnatal development in the cerebral cortex, group I mGlu receptors are excluded from the main body of the postsynaptic specialization (Fig. 4). Its highest concentration occurs at the edge of the postsynaptic specialization (termed perisynap- tic location), as well as along the extrasynaptic plasma membrane (López-Bendito et al., 2002a; Fig. 4). A similar distribution for mGlu1 and mGlu5 is seen in the adult (Luján et al., 1996, 1997; López-Bendito et al., 2002a). In the cerebellum, however, mGlu1 is already present in Purkinje cell spines before the arrival of excitatory synapses, and as development progresses, mGlu1 accumulates in perisynaptic positions, in association with the maturation of parallel fiber-Purkinje cell synapses (López-Bendito et al., 2001). The acquisition of group II and III mGlu receptors at synapses is unexplored. We mainly know their final localization in the adulthood. Here, group II mGlu receptors, mGlu2 and mGlu3, can be found both at postsynaptic and presynaptic sites (Fig. 4), depending on the 576 R. Luján et al. / Neuroscience 130 (2005) 567–580 brain region and cell type. At their postsynaptic location, mGlu2 is preferentially located outside the synapse (Luján et al., 1997). In contrast, mGlu3 is found to be associated with glutamatergic synapses, including the postsynaptic specialization, and glial cells (Tamaru et al., 2001; Fig. 4). At presynaptic locations, mGlu2 and mGlu3 are concentrated in the pre-terminal portion of axons or along the extrasynaptic membrane of axon terminals, and always outside the presynaptic active zone (Luján et al., 1997; Shigemoto et al., 1997; Tamaru et al., 2001; Fig. 4). Regarding group III mGlu receptors, mGlu4, mGlu7 and mGlu8 are mainly concentrated along the presynaptic active zone of glutamatergic (Shigemoto et al., 1996, 1997; Kinoshita et al., 1998; Corti et al., 2002; Dalezios et al., 2002; Somogyi et al., 2003) and GABAergic synapses (Corti et al., 2002; Dalezios et al., 2002; Somogyi et al., 2003; Fig. 4), where they may act as autoand heteroreceptors, respectively. No information is as yet available about the factors that control this differential targeting to different subcellular domains or their recruitment in inhibitory synapses during development. GABAergic synapses. The involvement of GABAA receptors in the construction of postsynaptic domains of inhibitory synapses is not fully known. GABAA receptors are concentrated at synapses opposite to GABA releasing terminals (Fig. 4), but receptor complexes containing only ␣- and -subunits form channels that are inserted in the plasma membrane (Gunther et al., 1995). While the ␥ subunits are not necessary for receptor assembly and translocation to the neuronal surface, they seem to be required for clustering of postsynaptic GABAA receptor subtypes (Essrich et al., 1998; Schweizer et al., 2003). GABAA receptor subunits are also located along the extrasynaptic plasma membrane of neurons (Fig. 4), generally at low densities (Nusser et al., 1995), although the ␦ subunit is localized exclusively at extrasynaptic sites (Nusser et al., 1998a; Fig. 4). Furthermore, some GABAA receptor subunits (e.g. the ␣6, 2/3 and ␥2 subunits) have also been found at glutamatergic synapses (Nusser et al., 1996, 1998a). No information is as yet available about the acquisition of GABAB receptors at synapses. They show, however, one of the most intriguing locations of all neurotransmitter receptors during postnatal development and adulthood. Electrophysiological, pharmacological and immunohistochemical studies have identified GABAB receptors on postsynaptic sites and on presynaptic GABAergic and glutamatergic axons (Misgeld et al., 1995). Early in postnatal development, GABAB receptors are located at extrasynaptic and perisynaptic sites, as well as at pre- and postsynaptic sites, similarly to the distribution observed in the adulthood (López-Bendito et al., 2002b; Panzanelli et al., 2004; Fig. 4). They are abundant on dendritic spines postsynaptic to glutamatergic axon terminals in the brain (Fritschy et al., 1999; Gonchar et al., 2001; López-Bendito et al., 2002b, 2004b; Kulik et al., 2002, 2003; Luján et al., 2004) and on the postsynaptic specialization (Billinton et al., 2001; Gonchar et al., 2001; Kulik et al., 2002). In contrast, GABAB receptors are rarely associated with syn- apses opposite to GABA releasing terminals (LópezBendito et al., 2002b, 2004b; Kulik et al., 2002, 2003; Luján et al., 2004). At their presynaptic location, GABAB receptors are found in the preterminal portion of axons, in the extrasynaptic membrane of axon terminals and in presynaptic active zones of glutamatergic and GABAergic synapses (López-Bendito et al., 2002b; Kulik et al., 2002, 2003; Luján et al., 2004; Fig. 4), where they likely act as heteroand autoreceptors, respectively. Concluding remarks A combination of electrophysiological, molecular, in situ hybridization and immunohistochemical techniques has begun to shed light on the role and distribution of neurotransmitter receptors in the developing brain. This review illuminates recent evidence showing how glutamate and GABA receptors exert different roles during primary nervous structure establishment prior to the emergence of their role in neurotransmission. In this way, the early activation of glutamate and GABA receptor subunits, expressed by several kinds of cells, appears to account for the regulation of proliferation, migration and differentiation during CNS development. Additionally, early expression of the receptor subunits accounts for their involvement in the establishment of synaptic contact and the refinement of neuronal circuits. Moreover, changes in the level of expression and distribution of neurotransmitter receptors are critical steps in normal synapse development, and abnormalities in these processes may be responsible for neural diseases. Which specific changes are critical to both normal development and disease processes remain to be defined. This may not be particularly easy because the molecular composition and functional properties of synapses are heterogeneous. Indeed, glutamate and GABA receptors can be targeted during synaptogenesis to any subcellular compartment of the neuronal surface, in a receptor subunit- and cell type-dependent manner. Presumably, the different neurotransmitter receptor subunits are targeted to specific subcellular compartments because their intrinsic properties are most suited for the physiological functions at those sites during development and in the adulthood. Continued identification of the molecular components of individual synapses promises to offer new insights on the mechanisms that control synaptogenesis processes and the signaling between neurons in the developing brain. A more complete understanding of the roles of the many neurotransmitter receptor subunits described in this review, and of the functional interaction with other signaling proteins, should provide an increasing understanding of brain development and neurological diseases. Acknowledgments— The authors are grateful to Diane Latawiec, MSc, for the English revision of the manuscript. This work was supported by grants from the Consejerı́a de Sanidad of the Junta de Comunidades de Castilla-La Mancha. REFERENCES Altman J (1969) Autoradiographic and histological studies of postnatal neurogenesis: IV. Cell proliferation and migration in the anterior R. Luján et al. / Neuroscience 130 (2005) 567–580 forebrain, with special reference to persisting neurogenesis in the olfactory bulb. J Comp Neurol 137:433– 457. Bahn S, Volk B, Wisden W (1994) Kainate receptor gene expression in the developing rat brain. J Neurosci 14:5525–5547. Barbin G, Pollard H, Gaiarsa JL, Ben-Ari Y (1993) Involvement of GABAA receptors in the outgrowth of cultured hippocampal neurons. Neurosci Lett 152:150 –154. Bardoul M, Drain MJ, Konig N (1998) Modulation of intracellular calcium in early neural cells by non-NMDA ionotropic glutamate receptors. Perspect Dev Neurobiol 5:353–371. Behar TN, Li YX, Tran HT, Ma W, Dunlap V, Scott C, Barker JL (1996) GABA stimulates chemotaxis and chemokinesis of embryonic cortical neurons via calcium-dependent mechanisms. J Neurosci 16:1808 –1818. Behar TN, Schaffner AE, Scott CA, O’Connell C, Barker JL (1998) Differential response of cortical plate and ventricular zone cells to GABA as a migration stimulus. J Neurosci 18:6378 – 6387. Behar TN, Scott CA, Greene CL, Wen X, Smith SV, Maric D, Liu QY, Colton CA, Barker JL (1999) Glutamate acting at NMDA receptors stimulates embryonic cortical neuronal migration. J Neurosci 19:4449 – 4461. Behar TN, Schaffner AE, Scott CA, Greene CL, Barker JL (2000) GABA receptor antagonists modulate postmitotic cell migration in slice cultures of embryonic rat cortex. Cereb Cortex 10:899 –909. Behar TN, Smith SV, Kennedy RT, McKenzie JM, Maric I, Barker JL (2001) GABA(B) receptors mediate motility signals for migrating embryonic cortical cells. Cereb Cortex 11:744 –753. Ben-Ari Y (2002) Excitatory actions of GABA during development: the nature of the nurture. Nat Rev Neurosci 3:728 –739. Benı́tez-Diaz P, Miranda-Contreras L, Mendoza-Briceño RV, PeñaContreras Z, Palacios-Prü E (2003) Prenatal and postnatal contents of amino acid neurotransmitters in mouse parietal cortex. Dev Neurosci 25:366 –374. Ben-Yaakov G, Golan H (2003) Cell proliferation in response to GABA in postnatal hippocampal slice culture. Int J Dev Neurosci 21:153–157. Brewer GJ, Cotman CW (1989) NMDA receptor regulation of neuronal morphology in cultured hippocampal neurons. Neurosci Lett 99:268 –273. Billinton A, Ige AO, Bolam JP, White JH, Marshall FH, Emson PC (2001) Advances in the molecular understanding of GABA(B) receptors. Trends Neurosci 24:277–282. Bolton MM, Blanpied TA, Ehlers MD (2000) Localization and stabilization of ionotropic glutamate receptors at synapses. Cell Mol Life Sci 57:1517–1525. Bowery NG, Bettler B, Frostl W, Gallagher JP, Marshall F, Raiteri M, Bonner TI, Enna SJ (2002) International Union of Pharmacology: XXXIII. Mammalian ␥-aminobutyric acidB receptors: structure and function. Pharmacol Rev 54:247–264. Bradley SR, Rees HD, Yi H, Levey AI, Conn PJ (1998) Distribution and developmental regulation of metabotropic glutamate receptor 7a in rat brain. J Neurochem 71:636 – 645. Cameron HA, McEwen BS, Gould E (1995) Regulation of adult neurogenesis by excitatory input and NMDA receptor activation in the dentate gyrus. J Neurosci 15:4687– 4692. Cameron HA, Hazel TG, McKay RD (1998) Regulation of neurogenesis by growth factors and neurotransmitters. J Neurobiol 36:287–306. Casabona G, Knopfel T, Kuhn R, Gasparini F, Baumann P, Sortino MA, Copani A, Nicoletti F (1997) Expression and coupling to polyphosphoinositide hydrolysis of group I metabotropic glutamate receptors in early postnatal and adult rat brain. Eur J Neurosci 9:12–17. Catania MV, Landwehrmeyer GB, Testa CM, Standaert DG, Penney JB Jr, Young AB (1994) Metabotropic glutamate receptors are differentially regulated during development. Neuroscience 61:481–495. Cohen-Cory S (2002) The developing synapse: construction and modulation of synaptic structures and circuits. Science 298:770 –776. 577 Conn PJ, Pin JP (1997) Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol 37:205–237. Corti C, Aldegheri L, Somogyi P, Ferraguti F (2002) Distribution and synaptic localisation of the metabotropic glutamate receptor 4 (mGluR4) in the rodent CNS. Neuroscience 110:403– 420. Couve A, Moss SJ, Pangalos MN (2000) GABAB receptors: a new paradigm in G protein signalling. Mol Cell Neurosci 16:296 –312. Culiat CT, Stubbs LJ, Montgomery CS, Russell LB, Rinchik EM (1994) Phenotypic consequences of deletion of the gamma 3, alpha 5, or beta 3 subunit of the type A gamma-aminobutyric acid receptor in mice. Proc Natl Acad Sci USA 91:2815–2818. Curran T, D’Arcangelo G (1998) Role of reelin in the control of brain development. Brain Res Brain Res Rev 26:285–294. Dalezios Y, Luján R, Shigemoto R, Roberts JDB, Somogyi P (2002) The presence of mGluR7a in the presynaptic active zones of GABAergic and non-GABAergic terminals on interneurones in the rat somatosensory cortex. Cereb Cortex 12:961–974. Darstein M, Petralia RS, Swanson GT, Wenthold RJ, Heinemann SF (2003) Distribution of kainate receptor subunits at hippocampal mossy fiber synapses. J Neurosci 23:8013– 8019. Demarque M, Represa A, Becq H, Khalilov I, Ben-Ari Y, Aniksztejn L (2002) Paracrine intercellular communication by a Ca2⫹- and SNARE-independent release of GABA and glutamate prior to synapse formation. Neuron 36:1051–1061. Di Giorgi Gerevini VD, Caruso A, Cappuccio I, Ricci Vitiani L, Romeo S, Della Rocca C, Gradini R, Melchiorri D, Nicoletti F (2004) The mGlu5 metabotropic glutamate receptor is expressed in zones of active neurogenesis of the embryonic and postnatal brain. Brain Res Dev Brain Res 150:17–22. Elezgarai I, Benitez R, Mateos JM, Lazaro E, Osorio A, Azkue JJ, Bilbao A, Lingenhoehl K, Van Der Putten H, Hampson DR, Kuhn R, Knopfel T, Grandes P (1999) Developmental expression of the group III metabotropic glutamate receptor mGluR4a in the medial nucleus of the trapezoid body of the rat. J Comp Neurol 411:431– 440. Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH (1998) Neurogenesis in the adult human hippocampus. Nat Med 4:1313–1317. Essrich C, Lorez M, Benson JA, Fritschy JM, Luscher B (1998) Postsynaptic clustering of major GABAA receptor subtypes requires the gamma 2 subunit and gephyrin. Nat Neurosci 1: 563–571. Fritschy JM, Paysan J, Enna A, Mohler H (1994) Switch in the expression of rat GABAA-receptor subtypes during postnatal development: an immunohistochemical study. J Neurosci 14: 5302–5324. Fritschy JM, Meskenaite V, Weinmann O, Honer M, Benke D, Mohler H (1999) GABAB-receptor splice variants GB1a and GB1b in rat brain: developmental regulation, cellular distribution and extrasynaptic localization. Eur J Neurosci 11:761–768. Fritschy JM, Schweizer C, Brunig I, Luscher B (2003) Pre- and postsynaptic mechanisms regulating the clustering of type A gammaaminobutyric acid receptors (GABAA receptors). Biochem Soc Trans 31:889 – 892. Frotscher M (1998) Cajal-Retzius cells, Reelin, and the formation of layers. Curr Opin Neurobiol 8:570 –575. Furuta A, Martin LJ (1999) Laminar segregation of the cortical plate during corticogenesis is accompanied by changes in glutamate receptor expression. J Neurobiol 39:67– 80. Garner CC, Zhai RG, Gundelfinger ED, Ziv NE (2002) Molecular mechanisms of CNS synaptogenesis. Trends Neurosci 25:243–251. Golshani P, Warren RA, Jones EG (1998) Progression of change in NMDA, non-NMDA, and metabotropic glutamate receptor function at the developing corticothalamic synapse. J Neurophysiol 80:143–154. Gonchar Y, Pang L, Malitschek B, Bettler B, Burkhalter A (2001) Subcellular localization of GABA(B) receptor subunits in rat visual cortex. J Comp Neurol 431:182–197. 578 R. Luján et al. / Neuroscience 130 (2005) 567–580 Gould E, Cameron HA, McEwen BS (1994) Blockade of NMDA receptors increases cell death and birth in the developing rat dentate gyrus. J Comp Neurol 340:551–565. Gould E, Tanapat P, McEwen BS, Flugge G, Fuchs E (1998) Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proc Natl Acad Sci USA 95:3168–3171. Gundersen V, Holten AT, Storm-Mathisen J (2004) GABAergic synapses in hippocampus exocytose aspartate on to NMDA receptors: quantitative immunogold evidence for co-transmission. Mol Cell Neurosci 26:156 –165. Gunther U, Benson J, Benke D, Fritschy JM, Reyes G, Knoflach F, Crestani F, Aguzzi A, Arigoni M, Lang Y (1995) Benzodiazepineinsensitive mice generated by targeted disruption of the gamma 2 subunit gene of gamma-aminobutyric acid type A receptors. Proc Natl Acad Sci USA 92:7749 –7753. Hall RA, Bahr BA (1994) AMPA receptor development in rat telencephalon: [3H]AMPA binding and Western blot studies. J Neurochem 63:1658 –1665. Hatten ME (1999) Central nervous system neuronal migration. Annu Rev Neurosci 22:511–539. Haydar TF, Wang F, Schwartz ML, Rakic P (2000) Differential modulation of proliferation in the neocortical ventricular and subventricular zones. J Neurosci 20:5764 –5774. Hollmann M, Heinemann S (1994) Cloned glutamate receptors. Annu Rev Neurosci 17:31–108. Killisch I, Dotti CG, Laurie DJ, Luddens H, Seeburg PH (1991) Expression patterns of GABAA receptor subtypes in developing hippocampal neurons. Neuron 7:927–936. Kim MO, Li S, Park MS, Hornung JP (2003) Early fetal expression of GABA(B1) and GABA(B2) receptor mRNAs on the development of the rat central nervous system. Brain Res Dev Brain Res 143:47–55. Kinoshita A, Shigemoto R, Ohishi H, van der Putten H, Mizuno N (1998) Immunohistochemical localization of metabotropic glutamate receptors, mGluR7a and mGluR7b, in the central nervous system of the adult rat and mouse: a light and electron microscopic study. J Comp Neurol 393:332–352. Komuro H, Rakic P (1993) Modulation of neuronal migration by NMDA receptors. Science 260:95–97. Kornack DR, Rakic P (2001) Cell proliferation without neurogenesis in adult primate neocortex. Science 294:2127–2130. Kulik A, Nakadate K, Nyiri G, Notomi T, Malitschek B, Bettler B, Shigemoto R (2002) Distinct localization of GABAB receptors relative to synaptic sites in the rat cerebellum and ventrobasal thalamus. Eur J Neurosci 15:291–307. Kulik A, Vida I, Luján R, Haas C, López-Bendito G, Shigemoto R, Frotscher M (2003) Subcellular localization of metabotropic GABAB receptor subunits GABAB1a/b and GABAB2 in the rat hippocampus. J Neurosci 23:11026 –11035. Lauder JM (1993) Neurotransmitters as growth regulatory signals: role of receptors and second messengers. Trends Neurosci 16:233–240. Laurie DJ, Wisden W, Seeburg PH (1992) The distribution of thirteen GABA A receptor subunit mRNAs in the rat brain: III. Embryonic and postnatal development. J Neurosci 12:4151– 4172. Lee SH, Sheng M (2000) Development of neuron-neuron synapses. Curr Opin Neurobiol 10:125–131. Lois C, Alvarez-Buylla A (1994) Long-distance neuronal migration in the adult mammalian brain. Science 264:1145–1148. López-Bendito G, Shigemoto R, Luján R, Juiz JM (2001) Developmental changes in the localisation of the mGluR1␣ subtype of metabotropic glutamate receptors in Purkinje cells. Neuroscience 105:413– 429. López-Bendito G, Shigemoto R, Fairén A, Luján R (2002a) Differential distribution of group I metabotropic glutamate receptors during rat cortical development. Cereb Cortex 12:625– 638. López-Bendito G, Shigemoto R, Kulik A, Paulsen O, Fairén A, Luján R (2002b) Expression and distribution of metabotropic GABA receptor subtypes GABABR1 and GABABR2 during rat neocortical development. Eur J Neurosci 15:1766 –1778. López-Bendito G, Luján R, Shigemoto R, Ganter P, Paulsen O, Molnár Z (2003): Blockade of GABAB receptors alters the tangential migration of cortical neurons. Cereb Cortex 13:932–942. López-Bendito G, Sturgess K, Erdelyi F, Szabo G, Molnar Z, Paulsen O (2004a) Preferential origin and layer destination of GAD65-GFP cortical interneurons. Cereb Cortex 14:1122–1133. López-Bendito G, Shigemoto R, Kulik A, Vida I, Fairén A, Luján R (2004b) Distribution of metabotropic GABAB receptor subunits GABAB1a/b and GABAB2 in the rat hippocampus during prenatal and postnatal development. Hippocampus 14:836 – 848. LoTurco JJ, Owens DF, Heath MJ, Davis MB, Kriegstein AR (1995) GABA and glutamate depolarize cortical progenitor cells and inhibit DNA synthesis. Neuron 15:1287–1298. Luján R, Nusser Z, Roberts JDB, Shigemoto R, Somogyi P (1996) Perisynaptic location of metabotropic glutamate receptors mGluR1 and mGluR5 on dendrites and dendritic spines in the rat hippocampus. Eur J Neurosci 8:1488 –1500. Luján R, Roberts JDB, Shigemoto R, Ohishi H, Somogyi P (1997) Differential plasma membrane distribution of metabotropic glutamate receptors mGluR1␣, mGluR2 and mGluR5, relative to neurotransmitter release sites. J Chem Neuroanat 13:219 –241. Luján R, Shigemoto R, Kulik A, Juiz JM (2004) Localisation of the GABAB receptor 1a/b subunit relative to glutamatergic synapses in the dorsal cochlear nucleus of the rat. J Comp Neurol 475:36 – 46. Luk KC, Kennedy TE, Sadikot AF (2003) Glutamate promotes proliferation of striatal neuronal progenitors by an NMDA receptormediated mechanism. J Neurosci 23:2239 –2250. Ma W, Barker JL (1995) Complementary expressions of transcripts encoding GAD67 and GABAA receptor alpha 4, beta 1, and gamma 1 subunits in the proliferative zone of the embryonic rat central nervous system. J Neurosci 15:2547–2560. Ma W, Liu QY, Maric D, Sathanoori R, Chang YH, Barker JL (1998) Basic FGF-responsive telencephalic precursor cells express functional GABA(A) receptor/Cl-channels in vitro. J Neurobiol 35:277–286. Macdonald RL, Olsen RW (1994) GABAA receptor channels. Annu Rev Neurosci 17:569 – 602. Maric D, Liu QY, Grant GM, Andreadis JD, Hu Q, Chang YH, Barker JL, Joseph J, Stenger DA, Ma W (2000) Functional ionotropic glutamate receptors emerge during terminal cell division and early neuronal differentiation of rat neuroepithelial cells. J Neurosci Res 61:652– 662. Maric D, Liu QY, Maric I, Chaudry S, Chang YH, Smith SV, Sieghart W, Fritschy JM, Barker JL (2001) GABA expression dominates neuronal lineage progression in the embryonic rat neocortex and facilitates neurite outgrowth via GABA(A) autoreceptor/Cl⫺ channels. J Neurosci 21:2343–2360. Marı́n O, Rubenstein JL (2001) A long, remarkable journey: tangential migration in the telencephalon. Nat Rev Neurosci 2:780 –790. Martin LJ, Furuta A, Blackstone CD (1998) AMPA receptor protein in developing rat brain: glutamate receptor-1 expression and localization change at regional, cellular, and subcellular levels with maturation. Neuroscience 83:917–928. Martin SC, Steiger JL, Gravielle MC, Lyons HR, Russek SJ, Farb DH (2004) Differential expression of gamma-aminobutyric acid type B receptor subunit mRNAs in the developing nervous system and receptor coupling to adenylyl cyclase in embryonic neurons. J Comp Neurol 473:16 –29. Martı́nez-Galán JR, López-Bendito G, Lujan R, Shigemoto R, Fairen A, Valdeolmillos M (2001) Cajal-Retzius cells in early postnatal mouse cortex selectively express functional metabotropic glutamate receptors. Eur J Neurosci 13:1147–1154. Marty S, Berninger B, Carroll P, Thoenen H (1996) GABAergic stimulation regulates the phenotype of hippocampal interneurons through the regulation of brain-derived neurotrophic factor. Neuron 16:565–570. Mattson MP, Lee RE, Adams ME, Guthrie PB, Kater SB (1988) Interactions between entorhinal axons and target hippocampal R. Luján et al. / Neuroscience 130 (2005) 567–580 neurons: a role for glutamate in the development of hippocampal circuitry. Neuron 1:865– 876. Meier J (2003) The enigma of transmitter-selective receptor accumulation at developing inhibitory synapses. Cell Tissue Res 311:271–276. Metin C, Denizot JP, Ropert N (2000) Intermediate zone cells express calcium-permeable AMPA receptors and establish close contact with growing axons. J Neurosci 20:696 –708. Mienville JM, Pesold C (1999) Low resting potential and postnatal upregulation of NMDA receptors may cause Cajal-Retzius cell death. J Neurosci 19:1636 –1646. Minakami R, Iida K, Hirakawa N, Sugiyama H (1995) The expression of two splice variants of metabotropic glutamate receptor subtype 5 in the rat brain and neuronal cells during development. J Neurochem 65:1536 –1542. Miranda-Contreras L, Mendoza-Briceno RV, Palacios-Pru EL (1998) Levels of monoamine and amino acid neurotransmitters in the developing male mouse hypothalamus and in histotypic hypothalamic cultures. Int J Dev Neurosci 16:403– 412. Miranda-Contreras L, Benitez-Diaz PR, Mendoza-Briceno RV, Delgado-Saez MC, Palacios-Pru EL (1999) Levels of amino acid neurotransmitters during mouse cerebellar neurogenesis and in histiotypic hypothalamic cultures. Dev Neurosci 12:147–158. Misgeld U, Bijak M, Jarolimek W (1995) A physiological role for GABAB receptors and the effects of baclofen in the mammalian central nervous system. Prog Neurobiol 46:423– 462. Miskevich F, Lu W, Lin SY, Constantine-Paton M (2002) Interaction between metabotropic and NMDA subtypes of glutamate receptors in sprout suppression at young synapses. J Neurosci 22:226 –238. Nery S, Fishell G, Corbin JG (2002) The caudal ganglionic eminence is a source of distinct cortical and subcortical cell populations. Nat Neurosci 5:1279 –1287. Nguyen L, Rigo JM, Rocher V, Belachew S, Malgrange B, Rogister B, Leprince P, Moonen G (2001) Neurotransmitters as early signals for central nervous system development. Cell Tissue Res 305:187–202. Nusser Z, Roberts JD, Baude A, Richards JG, Somogyi P (1995) Relative densities of synaptic and extrasynaptic GABAA receptors on cerebellar granule cells as determined by a quantitative immunogold method. J Neurosci 15:2948 –2960. Nusser Z, Sieghart W, Stephenson FA, Somogyi P (1996) The alpha 6 subunit of the GABAA receptor is concentrated in both inhibitory and excitatory synapses on cerebellar granule cells. J Neurosci 16:103–114. Nusser Z, Sieghart W, Somogyi P (1998a) Segregation of different GABAA receptors to synaptic and extrasynaptic membranes of cerebellar granule cells. J Neurosci 18:1693–1703. Nusser Z, Lujan R, Laube G, Roberts JD, Molnar E, Somogyi P (1998b) Cell type and pathway dependence of synaptic AMPA receptor number and variability in the hippocampus. Neuron 21:545–559. Owens DF, Kriegstein AR (2002) Is there more to GABA than synaptic inhibition? Nat Rev Neurosci 3:715–727. Panzanelli P, López-Bendito G, Luján R, Sassoe-Pogneto M (2004) Localization and developmental expression of GABAB receptors in the rat olfactory bulb. J Neurocytol 33:87–99. Parnavelas JG (2000) The origin and migration of cortical neurones: new vistas. Trends Neurosci 23:126 –131. Pearce IA, Cambray-Deakin MA, Burgoyne RD (1987) Glutamate acting on NMDA receptors stimulates neurite outgrowth from cerebellar granule cells. FEBS Lett 223:143–147. Petralia RS, Esteban JA, Wang YX, Partridge JG, Zhao HM, Wenthold RJ, Malinow R (1999) Selective acquisition of AMPA receptors over postnatal development suggests a molecular basis for silent synapses. Nat Neurosci 2:31–36. Pin JP, Duvoisin R (1995) The metabotropic glutamate receptors: structure and functions. Neuropharmacology 34:1–26. 579 Poluch S, Drian MJ, Durand M, Astier C, Benyamin Y, Konig N (2001) AMPA receptor activation leads to neurite retraction in tangentially migrating neurons in the intermediate zone of the embryonic rat neocortex. J Neurosci Res 63:35– 44. Racca C, Stephenson FA, Streit P, Roberts JD, Somogyi P (2000) NMDA receptor content of synapses in stratum radiatum of the hippocampal CA1 area. J Neurosci 20:2512–2522. Romano C, van den Pol AN, O’Malley KL (1996) Enhanced early developmental expression of the metabotropic glutamate receptor mGluR5 in rat brain: protein, mRNA splice variants, and regional distribution. J Comp Neurol 367:403– 412. Romano C, Smout S, Miller JK, O’Malley KL (2002) Developmental regulation of metabotropic glutamate receptor 5b protein in rodent brain. Neuroscience 111:693– 698. Rossi DJ, Slater NT (1993) The developmental onset of NMDA receptor-channel activity during neuronal migration. Neuropharmacology 32:1239 –1248. Schwartz TH, Rabinowitz D, Unni V, Kumar VS, Smetters DK, Tsiola A, Yuste R (1998) Networks of coactive neurons in developing layer 1. Neuron 20:541–552. Schweizer C, Balsiger S, Bluethmann H, Mansuy IM, Fritschy JM, Mohler H, Luscher B (2003) The gamma 2 subunit of GABA(A) receptors is required for maintenance of receptors at mature synapses. Mol Cell Neurosci 24:442– 450. Serafini R, Maric D, Maric I, Ma W, Fritschy JM, Zhang L, Barker JL (1998) Dominant GABA(A) receptor/Cl⫺ channel kinetics correlate with the relative expressions of alpha2, alpha3, alpha5 and beta3 subunits in embryonic rat neurones. Eur J Neurosci 10:334 –349. Shigemoto R, Nakanishi S, Mizuno N (1992) Distribution of the mRNA for a metabotropic glutamate receptor (mGluR1) in the central nervous system: an in situ hybridization study in adult and developing rat. J Comp Neurol 322:121–135. Shigemoto R, Kulik A, Roberts JD, Ohishi H, Nusser Z, Kaneko T, Somogyi P (1996) Target-cell-specific concentration of a metabotropic glutamate receptor in the presynaptic active zone. Nature 381:523–525. Shigemoto R, Kinoshita A, Wada E, Nomura S, Ohishi H, Takada M, Flor PJ, Neki A, Abe T, Nakanishi S, Mizuno N (1997) Differential presynaptic localization of metabotropic glutamate receptor subtypes in the rat hippocampus. J Neurosci 17:7503–7522. Somogyi P, Tamas G, Lujan R, Buhl EH (1998) Salient features of synaptic organisation in the cerebral cortex. Brain Res Brain Res Rev 26:113–135. Somogyi P, Dalezios Y, Luján R, Roberts JDB, Watanabe M, Shigemoto R (2003) High level of mGluR7 in the presynaptic active zones of select populations of GABAergic terminals innervating interneurons in the rat hippocampus. Eur J Neurosci 17:2503–2520. Soria JM, Valdeolmillos M (2002) Receptor-activated calcium signals in tangentially migrating cortical cells. Cereb Cortex 12:831– 839. Sun L, Margolis FL, Shipley MT, Lidow MS (1998) Identification of a long variant of mRNA encoding the NR3 subunit of the NMDA receptor: its regional distribution and developmental expression in the rat brain. FEBS Lett 441:392–396. Takai H, Katayama K, Uetsuka K, Nakayama H, Doi K (2003) Distribution of N-methyl-D-aspartate receptors (NMDARs) in the developing rat brain. Exp Mol Pathol 75:89 –94. Tamaru Y, Nomura S, Mizuno N, Shigemoto R (2001) Distribution of metabotropic glutamate receptor mGluR3 in the mouse CNS: differential location relative to pre- and postsynaptic sites. Neuroscience 106:481–503. Tissir F, Goffinet AM (2003) Reelin and brain development. Nat Rev Neurosci 4:496 –505. Verkhratsky A, Steinhauser C (2000) Ion channels in glial cells. Brain Res Brain Res Rev 32:380 – 412. Wang DD, Krueger DD, Bordey A (2003) GABA depolarizes neuronal progenitors of the postnatal subventricular zone via GABAA receptor activation. J Physiol 550:785– 800. 580 R. Luján et al. / Neuroscience 130 (2005) 567–580 Walsh CA, Goffinet AM (2000) Potential mechanisms of mutations that affect neuronal migration in man and mouse. Curr Opin Genet Dev 10:270 –274. Watanabe M, Inoue Y, Sakimura K, Mishina M (1993) Distinct spatiotemporal distributions of the NMDA receptor channel subunit mRNAs in the brain. Ann NY Acad Sci 707:463– 466. Wilson MT, Kisaalita WS, Keith CH (2000) Glutamate-induced changes in the pattern of hippocampal dendrite outgrowth: a role for calcium-dependent pathways and the microtubule cytoskeleton. J Neurobiol 43:159 –172. Zhang LI, Poo MM (2001) Electrical activity and development of neural circuits. Nat Neurosci 4:1207–1214. (Accepted 23 September 2004) (Available online 11 November 2004)